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Researchers from Harvard Medical School and Massachusetts General Hospital have taken an important step toward improving the success of hand, face and other transplants that involve multiple types of tissue.

In its report in the American Journal of Transplantation, the team described how a procedure developed at Mass General to induce immune tolerance to organ transplants also induces tolerance to a model limb transplant in miniature swine.

Transplantation of donor bone marrow either several months before or at the same time as the transplant allowed the animals to accept what are called vascularized composite allografts (VCAs) from immunologically mismatched donors.

“The need for lifelong immunosuppression to prevent graft rejection is the most important challenge in this type of procedure, since most potential VCA recipients are young and would face increased risks of infection, diabetes or kidney problems, and even some types of cancer, over many years,” said senior author Curtis L. Cetrulo, Jr., HMS instructor in surgery at Mass General and head of the hospital’s Hand Transplantation Service.

“Bringing immunologic tolerance to hand and face transplantation would result in a paradigm shift in the way we will be able to treat the horrific injuries our service members are sustaining in the current military conflicts in Iraq and Afghanistan, as well for the types of blast-injury extremity loss seen in the Boston Marathon bombing,” he said. “Tolerance would give us a unique tool—a real game changer—with which to help these patients.”

Most frequently used to replace amputated hands and arms and to repair severe facial injuries, VCAs involve transplantation of muscle, bone, skin and nerves. While the procedures offer significant improvement in recipients’ quality of life, they do not in themselves save lives. That makes choosing lifelong immunosuppression more difficult. Inducing immune tolerance—essentially tricking a recipient’s immune system into accepting donor tissue—could be an ideal solution to that problem.

Protocol in Patients

Mass General is a world leader in the development of tolerance-inducing protocols, dating back to several decades of research led by David H. Sachs, the Paul S. Russell/Warner Lambert Professor of Surgery at Mass General and founder and scientific director of the hospital’s Transplantation Biology Research Center. He created an experimental protocol in which transplant recipients received both the needed organ and bone marrow from a living donor. This produced a state called mixed chimerism, in which the patient’s immune system contained both donor and recipient elements.

A number of patients who received kidney transplants using versions of this protocol were later able to stop taking immunosuppressive drugs. Most of these patients have been able to remain off immunosuppressive medications long term, some for more than a decade.

The current study was designed to test whether a similar protocol could induce tolerance to VCAs from immunologically mismatched donors in an animal model. VCAs pose an additional challenge because they include skin, which carries what could be considered its own immune system. In several previous attempts to induce VCA tolerance, bone and muscle tissue were accepted but the skin was rejected, eventually separating from the underlying tissue.

Chimerism

In the first phase of the study, four animals received bone marrow transplants from immunologically mismatched donors in advance, allowing time to confirm that chimerism had been established before the VCA procedure.

Transplantation of components of hind limbs from the same donors was carried out three to five months later. Even though they received no immunosuppression after the procedure, each animal accepted its transplant with no sign of rejection.

Because pre-transplant induction of chimerism would not be practical for hand or face transplants from deceased donors, in the second phase of the study the researchers tested VCA surgery conducted simultaneously with bone marrow transplantation to induce tolerance in two recipient animals.

Chimerism was successfully induced in both recipients, and overall results were the same as in the other group: immune tolerance of all components of the VCA with no evidence of rejection throughout the follow-up period, which for one recipient lasted more than 480 days.

Timing

In both groups of animals, the immune systems were conditioned to accept donor immune cells. Because the availability of donor tissues cannot be precisely predicted, Cetrulo explained, his team is exploring two approaches to the issue of timing the procedures.

In one approach, immune conditioning begins as soon as a donor is identified and the transplant confirmed. Conditioning continues during and immediately after a simultaneous bone marrow transplant/VCA procedure.

The second approach adapts a protocol developed for organ transplantation in which the recipient receives conventional immunosuppression after VCA surgery. Immune conditioning and transplantation of donor marrow collected at the time of VCA are performed several months later.

“Along with investigating the role of skin-specific immunobiology in VCA tolerance, with the aim of identifying mechanisms that might by harnessed by clinical protocols of the future, we’ll be conducting preclinical evaluation of both tolerance preconditioning protocols, which, if successful, could be ready for testing in a clinical trial within the next year,” said Cetrulo.

Funding for the study included National Institutes of Health grants P01CA111519 and R01AI084657, along with support from the Musculoskeletal Transplant Foundation and the Melina Nakos Foundation.